Rituximab Maintenance for 2 Years in Patients with Untreated High Tumor Burden Follicular Lymphoma After Response to Immunochemotherapy

G. A. Salles, J. F. Seymour, P. Feugier, F. Offner, A. Lopez-Guillermo, R. Bouabdallah,

L. M. Pedersen, P. Brice, D. Belada, L. Xerri on behalf of the PRIMA investigators

Gilles Salles Hospices Civils de Lyon

& Université Claude Bernard, Lyon, France

• Although FL remains incurable, patients may benefit from prolonged remission intervals; recent progress in response rate and response duration have translated into an improved survival

• Previous studies have demonstrated a significant clinical benefit using rituximab maintenance:

– In relapsing patients after chemo or R-chemo

– In first line patients after chemo alone or rituximab alone

– … but the role of rituximab after R-chemo in first line remains unknown

• PRIMA: an international and intergroup study Phase III randomized study

– Coordinated by GELA, in collaboration with European and Australian study groups and individual centers in Europe, Middle East, South America, and Asia, who collected, cleaned and analyzed the data

– With support from Roche

Primary RItuximab and MAintenance (PRIMA): Rationale

PRIMA: study design

PD/SDoff study

Rituximab maintenance375 mg/m2

every 8 weeks for 2 years‡

Observation‡

CR/CRuPR

Random 1:1*

Immunochemotherapy8 x Rituximab

+8 x CVP or

6 x CHOP or6 x FCM

High tumor burden

untreated follicular lymphoma

INDUCTION MAINTENANCE

Registration

* Stratified by response after induction, regimen of chemo, and geographic region‡ Frequency of clinical, biological and CT-scan assessments identical in both armsFive additional years of follow-up

PRIMA: Inclusion criteria

• Patients over 18 years previously untreated with histologically confirmed follicular lymphoma grade 1, 2 or 3a

• Patients with at least one of the following symptoms requiring initiationof treatment:

– Bulky disease at study entry (nodal or extranodal mass > 7cm)– Involvement of ≥ 3 nodal sites (each > 3 cm) – Symptomatic splenic enlargement, compressive syndrome,

pleural/peritoneal effusion – B symptoms presence– Elevated serum LDH (> ULN) or 2-microglobulin (> 3mg/L)

• ECOG performance status < 2• Written informed consent

ClinicalTrials.gov: NCT00140582

PRIMA: Exclusion criteria

• Transformation to high-grade lymphoma or Grade 3b follicular lymphoma• Regular corticosteroids during the last 4 weeks (> 20 mg/day prednisone)• Prior or concomitant malignancies• Serious underlying medical conditions or poor renal or hepatic function• Known HIV infection; active HBV or HCV infection• Known sensitivity or allergy to murine products

ClinicalTrials.gov: NCT00140582

• Primary endpoint:

– Progression-free survival (PFS) from randomization (to rituximab maintenance or observation)

• Secondary endpoints:

– event-free survival (EFS), overall survival (OS)

– time to next anti-lymphoma treatment (TTNLT), time to next chemotherapy (TTNCT)

– response rates at end of maintenance

– safety and toxicity

– quality of life (QoL) (FACT-G and EORTC scales)

• An Independent Review Committee (IRC) also examined all response and progression data (CT scans + clinical/biological findings)

PRIMA: Study endpoints

ClinicalTrials.gov: NCT00140582

• Sample size calculation:

– Based on a 45% increase in median PFS, with a power of 80% to detect this difference (type I alpha risk - 2-sided - of 5%)

– 1200 patients registered at induction, estimated response rate of 75%:

• 900 randomized to maintenance or observation (1:1)

• Full analysis after 344 events

• Interim analysis planned after 258 events:

– Stopping rules: two-sided O’Brien-Fleming boundary of 2.3397 with type I of 5% (nominal p = 0.0193)

– Analyzed by a third party statistician and submitted to an independent Data Safety Monitoring Committee (DSMC)

PRIMA: Statistical assumptions

ClinicalTrials.gov: NCT00140582

R-CHOPN = 885

Randomized N = 769

* 15 pts in 3 sites closed prematurely

Patients evaluable (N = 1202)*

R-CVPN = 272

Patients registered: N = 1217

R-FCMN = 45

RandomizedN = 222

Randomized N = 28

ObservationN = 513

RituximabN = 505

‡ 1 pt died during the randomization process

Ind

uct

ion

Mai

nte

nan

ce

9 pts did not receive chemo

147 pts withdrew during or at the end of induction (failure to respond; toxicity)

28 pts failed to be randomized

Patient disposition

Patients randomized: N = 1018‡

Pat

ien

ts (

%)

Patient demographics and tumor characteristics

5156

3033

2832

19

5853 54

3236

32 34

20

56

0

20

40

60

Median Age(yrs)

Male BM positive(%)

B symptoms(%)

PS ECOG >0(%)

β2m 3mg/L (%)

LDH >ULN(%)

Hb <12g/dL(%)

Observation n = 513 Rituximab maintenance n = 505

(%)

(2) (≥3)

Induction chemotherapy Response to inductionFLIPI at registration

(≤1)

Patient demographics and tumor characteristics (cont)

21

3642

75

22

3

3832

29

1

36

43

76

22

3

40

3128

2

21

0

10

20

30

40

50

60

70

80

Low Intermediate High R-CHOP R-CVP R-FCM CR CRu PR SD/Notevaluated

Observation n = 513 Rituximab maintenance n = 505

Pat

ien

ts (

%)

Primary endpoint (PFS) met at the planned interim analysis

Rituximab maintenance significantly reduced the risk of progression by 50%

stratified HR=0.50 95% CI 0.39; 0.64p<.0001

Time (months)

Rituximab maintenanceN=505

ObservationN=513

60 12 18 24 30 36

Pro

gre

ssio

n-f

ree

rate 0.8

0.6

0.4

0.2

0

1.0

82%

66%

Patients at risk

505

513

472 443 336 230 103 18

469 411 289 195 82 15

Benefits of rituximab maintenance seen in all major sub-groups evaluated

Subgroup Hazard ratioCategory 95% CIsHazard ratio*N

1018

624

394

216

370

431

768

222

28

721

290

0.38–0.64

0.33–0.62

0.39–0.90

0.19–0.77

0.25–0.61

0.43–0.67

0.31–0.59

0.44–1.08

0.13–2.07

0.38–0.70

0.29–0.72

0.49

0.45

0.59

0.38

0.39

0.61

0.43

0.69

0.51

0.52

0.45

All

< 60≥ 60

FLIPl = 2

FLIPl ≤ 1

FLIPl ≥ 3

R-CHOPR-CVP

R-FCM

CR/CRuPR

0 1 2 3

Response to Induction

Induction Chemotherapy

FLIPl Index

Age

All

* Non-stratified analysis

Favors maintenance Favors observation

Consistent results across secondary endpoints

513

505

487 447 327 218 87 15

483 453 349 235 103 18

Time (months)

60 12 18 24 30 360

Eve

nt-

free

rat

e 0.8

0.6

0.4

0.2

0

1.0

Patients at risk

513

505

492 454 332 225 91 17

484 457 351 243 108 19

Time (months)

60 12 18 24 30 360E

ven

t-fr

ee r

ate 0.8

0.6

0.4

0.2

0

1.0

Time to nextanti-lymphoma treatment

Time to nextchemotherapy treatment

HR = 0.61p = 0.0003

Rituximabmaintenance

ObservationHR = 0.60p = 0.0011

Observation

Rituximabmaintenance

ObservationObservation

Response status at end of maintenance

Observationn = 398 *

Rituximabn = 389 *

Progressive disease (PD) 162 (40.7%) 79 (20.3%)

Stable disease (SD) 1 (0.3%) 0 (0%)

Partial response (PR) 29 (7.3%) 28 (7.2%)

Complete response (CR/CRu) 190 (47.7%) 260 (66.8%)

* Patients not evaluated/missing data: respectively 16 and 22 pts‡ not evaluated in the rituximab maintenance arm: 2 pts

Response: end of Induction → Maintenance n = 190 n = 258 ‡

Patients remaining in CR/CRu 153 (56%) 209 (75%)

Patients converting from PR/SD to CR/CRu 37 (30%) 49 (45%)

Rituximab maintenance (n = 501)

Observation (n = 508)

Safety during rituximab maintenance

52

37

Any adverseevent

Grade 3/4neutropenia

Grade 3/4infections

Grade ≥2infections

Pat

ien

ts (

%)

100

80

60

40

20

0<1 4 <1 4

23

Grade 3/4adverse events

<1

3522

16

• At the time of analysis:

– Few patients withdrew for toxicity-related reasons during rituximab maintenance

• 1 patient in the observation arm• 10 patients in the maintenance arm

– 18 and 13 deaths*, respectively, had occurred in the observation and rituximab maintenance arms

• 12 related to lymphoma in the observation• 10 related to lymphoma in the maintenance arm

Safety during rituximab maintenance (cont)

(*) 3 additional deaths in the maintenance arm in patients that did not receive rituximab

Summary

• Rituximab maintenance for 2 years significantly improved PFS for patients with previously untreated FL who responded to induction with chemotherapy plus rituximab

• Benefits of rituximab maintenance seen in all major sub-groups

• Consistent improvements in secondary endpoints including EFS, TNLT, TNCT, ORR and CR rate at the end of maintenance

• IRC-assessed endpoints were consistent (not shown)

• Safety of maintenance was consistent with the known safety profile of rituximab, with no new or unexpected findings

• Additional follow-up will allow evaluation of a possible effect on overall survival

Conclusions

• The benefit of rituximab maintenance in first line appears superior to that described in relapsing patients:

– After R-CHOP in the EORTC study* HR = 0.69

– After R-CHOP in PRIMA HR = 0.43

• R-chemo followed by 2 years of rituximab maintenance

– Represents a new standard of care for FL patients in need of treatment

– Constitutes a new platform to further develop more efficient(and well tolerated) strategies

* van Oers MHJ, et al. J Clin Oncol 2010; ePub ahead of print.

Ackowledgements

• All the investigators and their staff from 223 centers in 25 countries

• Other cooperative groups in Australia/New Zealand, Spain, Czech Republic, UK and the Netherlands and several key investigators in various countries that made this study possible

• The GELA and GELA-RC teams for organization, monitoring, data cleaning and statistics

Latin America 76

France 624

Belgium 75Portugal 16Spain 54

Czech Republic 36

Denmark 48

U.K / Netherlands 34

Croatia / Serbia 16

Finland 24

India / China / Thailand 40

Australia / New Zaeland 158

Israel / Turkey 16

• Pathology review: L Xerri, N Brousse, D Canioni, F Charlotte, C Chassagne-Clément,P Dartigues, B Fabiani, L Deleval, E Campos, D DeJong

• DMSC members: J Armitage, D Hasenclever, M Ghielmini

• Roche team for their support, especially C Berge, J Maurer, M Mendila, M Wenger,O Manzke & S Zurfluh

Backup slides

PRIMA: Cox multivariate analysis

Covariate included in the modelHazard

Ratio95% CI for

Hazard Ratiop-value

Randomization treatment (R vs. O) 0.50 [0.39;0.64] <.0001

Age (>60 years vs. <60 years) 0.54 [0.49;0.83] .0010

FLIPI (low vs. intermediate/high) 0.62 [0.42;0.90] .0117

FLIPI (high vs. low/intermediate) 1.42 [1.08;1.87] .0121

Induction treatment (R-CHOP vs R-CVP/R-FCM) 0.63 [0.48;0.81] .0004

PFS, Stepwise Backward Selection Procedure, n=1018

Patient demography at induction

R-CHOPn = 881

R-CVPn = 268

R-FCMn = 44

Male 463 (53%) 137 (51%) 22 (50%)

Female 418 (47%) 131 (49%) 22 (50%)

Age (years) at registration

Mean (min–max) 55.4 (22–80) 57 (22–87) 51.3 (29–74)

Median 56 57.5 50

FLIPI score

0–1 193 (22%) 54 (21%) 7 (16%)

2 312 (35%) 91 (34%) 20 (45%)

3–5 375 (43%) 122 (45%) 17 (39%)

n 880 267 44

Patient demography at induction (cont)

R-CHOPn = 881

R-CVPn = 268

R-FCMn = 44

Performance status (ECOG scale)

0 574 (65%) 161 (60%) 24 (55%)

1 272 (31%) 94 (35%) 16 (36%)

2 35 (4%) 13 (5%) 4 (9%)

Ann Arbor stage

I 19 (2%) 4 (1%) -

II 68 (8%) 22 (8%) 5 (11%)

III 167 (19%) 53 (20%) 7 (16%)

IV 627 (71%) 189 (71%) 32 (73%)

Investigator-assessed response at end of induction

R-CHOPn = 881

R-CVPn = 268

R-FCMn = 44

Responders 818 (92.8%) 227 (84.7%) 33 (75.0%)

Non-responders 63 (7.2%) 41 (15.3%) 11 (25.0%)

95% CI for response rates [90.9; 94.5] [79.8; 88.8] [59.7; 86.8]

67

26

3 5

53

32

510

61

14

5

21

0

10

20

30

40

50

60

70

CR/CRu PR SD/PD NE/withdrawn

R-CHOP

R-CVP

R-FCM

PFS followingR-CHOP induction

Time (months)

Rituximab maintenance

Observation

60 12 18 24 30 36

Ev

en

t-fr

ee

ra

te

0.8

0.6

0.4

0.2

0

1.0

42

Time (months)

Rituximab maintenance

Observation

60 12 18 24 30 36E

ve

nt-

fre

e r

ate

0.8

0.6

0.4

0.2

0

1.0

42

Observation 388 385 361 321 222 153 64 18 113 113 99 87 63 44 19 0

Number left

Rituximabmaintenance 383 383 362 344 262 154 84 17 109 109 97 90 69 46 20 2

PFS followingR-CVP induction

Benefits of rituximab maintenance seen in major sub-groups evaluated

88%

68%

71%

61%

Rituximab maintenance does not adversely affect quality of life

Rituximab maintenance Observation

0

10

20

30

40

50

60

70

80

90

100

Glo

bal

Hea

lth

Sta

tus

scal

e

BL AI +1YEOT1Y BL AI +1YEOT1Y

BL =baselineAI = after induction1Y = 1 year of treatment

n 374 337 174 146 5304 341 218 177 13

EOT = end of treatment+1Y = 1 year after end of treatment

304 341 218 177 13

Immunoglobulin levels during maintenance / observation

IgG IgA

IgM

Imm

un

og

lob

ulin

G (

G/L

) 12

10

8

6

4

Baseline Visit 3 Visit 6 Visit 12 Assess end trt

Imm

un

og

lob

ulin

A (

G/L

) 6

3

0

-3

Observation / n = 508 Rituximab / n = 501

Imm

un

og

lob

ulin

M (

G/L

)

0.0

0.3

0.6

0.9

1.2

1.5

Baseline Visit 3 Visit 6 Visit 12 Assess end trt

Baseline Visit 3 Visit 6 Visit 12 Assess end trt

Laboratory values during maintenance/observation

Neutrophils Platelets

Lymphocytes

Neu

trop

hils (

10

**9

/L)

12

Base-line

11109876543210

2 3 4 5 6 7 8 9 10 11 12 Endtrt

Pla

tele

ts (

10

**9

/L)

0

100

200

300

400

500600

700

800

900

1000

Lym

ph

ocyte

s (

10

**g

/L)

0

1

2

3

4

5

6

7

8

Observation / n = 508 Rituximab / n = 501

VISIT

Base-line

2 3 4 5 6 7 8 9 10 11 12 EndtrtVISIT

Base-line

2 3 4 5 6 7 8 9 10 11 12 EndtrtVISIT